Alkyl amino acid derivatives useful as pharmaceutical agents

ABSTRACT

GABA-related pro-drugs of the formula (III) are provided that when administered to humans or other mammals provide an increased duration of active compound in the plasma compared to compounds of corresponding structure in which labile groups are not present. The compounds are of the formula (III)  
                 
 
     In the above formula:  
     P represents hydrogen or methyl;  
     Q represents a labile amine- or amide-forming organic group that becomes removed in the human or animal body;  
     R 1  represents straight or branched C 2 -C 6  alkyl, C 3 -C 6  cycloalkyl or phenyl;  
     R 2  represents hydrogen or methyl; and  
     R 3  represents hydrogen, methyl or carboxyl; and  
     R 4  represents hydrogen or a labile ester-forming group selected from substituted and unsubstituted C 1 -C 6  alkyl, benzyl and phenyl groups that become removed in the human or animal body. In the above formula when R 1  is phenyl, R 2 , R 3  and R 4  are not simultaneously hydrogen. Pharmaceutically acceptable salts of any salt-forming compound within the above class are also included. The compounds may be used to treat a range of neurological conditions, e.g. epilepsy and pain.

FIELD OF THE INVENTION

[0001] This invention relates to novel alkyl amino acid derivativesuseful as pharmaceutical agents, to processes for their production, topharmaceutical compositions containing them, and to their use for thetreatment of the neurological conditions set out below.

BACKGROUND TO THE INVENTION

[0002] U.S. Pat. No. 5,563,175 describes compounds of the formula (I)

[0003] in which:

[0004] R¹ represents straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkylor phenyl;

[0005] R² represents hydrogen or methyl; and

[0006] R³ represents hydrogen, methyl or carboxyl.

[0007] The compounds (including their pharmaceutically acceptable salts)are analogues of γ-aminobutyric acid (GABA) and were stated to activateGAD, to bind to a novel binding site, to be useful in anti-seizuretherapy for central nervous system disorders such as epilepsy,Huntington's chorea, cerebral ischemia, Parkinson's disease, tardivediskinesia and spasticity, and also to exhibit antidepressant,anxiolytic and antipsychotic activity. The most preferred compounds werethose where R³ and R² were hydrogen and R¹ was isobutyl, the (S)-(+)enantiomer of formula (II) being the most preferred.

[0008] That compound is variously called4-amino-3-(2-methylpropyl)butanoic acid,3-(aminomethyl)-5-methylhexanoic acid, β-isobutyl-65 -aminobutyric acid,isobutyl-GABA, isobutylgaba and pregabalin.

[0009] U.S. Pat. No. 6,001,876 discloses that the above compounds areuseful in pain therapy. U.S. Pat. No. 5,840,956 discloses methods formaking (±)-isobutylgaba and for obtaining from it (S)-isobutylgaba. Thedisclosures of all the above patents are hereby incorporated byreference.

SUMMARY OF THE INVENTION

[0010] A problem with which this invention is concerned is theproduction of compounds useful in the manner of pregabalin, especiallyin pain therapy, that when administered to humans or other animalsprovide an increased duration of active ingredient in the plasma.

[0011] That problem is unexpectedly solved, according to the invention,by pro-drugs of pregabalin the compounds of the formula (III)

[0012] in which:

[0013] P is hydrogen or methyl;

[0014] Q is a labile amine- or amide-forming organic group that becomesremoved in the human or animal body;

[0015] R¹ is straight or branched C₂-C₆ alkyl, C₃-C₆ cycloalkyl orphenyl;

[0016] R² is hydrogen or methyl; and

[0017] R³ is hydrogen, methyl or carboxyl;

[0018] R⁴ is hydrogen or a labile ester-forming group selected fromsubstituted and unsubstituted C₁-C₆ alkyl, benzyl and phenyl groups thatbecome removed in the human or animal body, and

[0019] a pharmaceutically acceptable salt of any salt-forming compoundwithin the above class,

[0020] but excluding compounds in which R¹ is phenyl and R², R³ and R⁴are each hydrogen.

[0021] It is believed that a pro-drug of the above formula whenadministered to a human or other animal, especially a mammal, enters thebloodstream by passive diffusion along the whole length of theintestine, which gives a much longer duration of effectiveness. Thepro-drug may not itself be biologically active, but decomposes to thecorresponding active compound in plasma.

[0022] Certain of the compounds of the invention can exist in unsolvatedforms as well as solvated forms, including hydrated forms. In general,the solvated forms, including hydrated forms, are biologicallyequivalent to unsolvated forms and are encompassed within the scope ofthe invention. Certain of the compounds of the invention possess one ormore chiral centers and each center may exist in the R or Sconfiguration. The invention includes all enantiomeric and epimericforms as well as the appropriate mixtures thereof. It also includessalts of any of the above compounds with physiologically acceptablecations or anions.

[0023] The invention also provides a method for making a compound of theformula (III) above, which comprises:

[0024] coupling a compound of the formula:

[0025] in which P and R¹-R⁴ have the meanings given above and in whichsaid compound is in the form of a free base or an ammonium salt with acompound of the formula (VI)

[0026] or QCl, where (in each case) Q has the meaning given above;

[0027] and the invention also provides a method for making a compound ofthe formula (III) above, which comprises coupling a compound of theformula (V) that is a carboxylic acid, optionally employing the furtherstep of esterifying the carboxyl group with a substituted orunsubstituted C₁-C₆ alkanol, benzyl alcohol or phenol.

[0028] The invention also provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of formula(III) above and a pharmaceutically acceptable carrier.

[0029] In a further aspect the invention provides the use of a compoundof formula (III) in the manufacture of a medicament for the treatment ofany of the following: epilepsy; a faintness attack; hypokinesia; acranial disorder; a neurodegenerative disorder; depression; anxiety;panic; pain; a neuropathological disorder; a digestive disorder.

[0030] In a further aspect, the invention provides a method for treatingany of the above disorders which comprises administering atherapeutically effective amount of a compound of formula (III) to ahuman or animal in need of said treatment.

DESCRIPTION OF PREFERRED FEATURES

[0031] One class of pro-drugs of the invention, which is preferred onaccount of the relatively high activity of the parent compound,comprises isobutylgaba pro-drugs of the formula (IV)

[0032] in which P, Q and R⁴ have the meanings given above, andpharmaceutically acceptable salts of any salt-forming compound withinthe above class.

[0033] Where R⁴ is not hydrogen, it is desirable that it should be morelabile than Q so that under physiological conditions the free acid formsfirst and unwanted reactions between the amino and carboxyl groups areavoided. Suitable values of R⁴ other than hydrogen are ethyl,iso-propyl, benzyl, phenyl, methyl and t-butyl.

[0034] The group Q may be one which can be removed hydrolytically underphysiological conditions, in which case it may be

[0035] in which:

[0036] R⁵ is hydrogen, straight or branched chain C₁-C₆ alkyl, phenyl orbenzyl in which the benzene ring may be substituted or unsubstituted;and

[0037] Y is hydrogen, straight or branched chain C₁-C₆ alkyl, or—CH₂CO₂R⁶ in which R⁶ represents straight or branched chain C₁-C₆ alkyl

[0038] Alternatively, the group Q may be one which can be removedenzymatically under physiological conditions, in which case it may beselected from

[0039] in which:

[0040] R⁷ is hydrogen, straight or branched chain, phenyl or benzyl inwhich either or each benzene ring may be substituted or unsubstituted;and

[0041] X represents a phenyl group or any of the side chains of the 20naturally encoded α-amino acids.

[0042] In a preferred group of compounds Q is

[0043] wherein R⁷ is C₁-C₆ alkyl (preferably methyl or t-butyl) orphenyl.

[0044] Compounds according to the invention include inter alia:

[0045] (S)-3-(Benzoylaminomethyl)-5-methylhexanoic acid;

[0046] (S)-Benzyl 3-(acylaminomethyl)-5-methylhexanoate;

[0047](S)-3-[N-(acetoxymethyleneoxycarbonyl)aminomethyl]-5-methylhexanoicacid;

[0048](S)-3-[N-((2,2-dimethylpropionyloxy)methyleneoxycarbonyl)-aminomethyl]-5-methylhexanoicacid;

[0049](S)-3-[N-(benzoyloxymethyleneoxycarbonyl)aminomethyl]-5-methylhexanoicacid;and

[0050] pharmaceutically acceptable salts of any of the above.

[0051] Various methods may be used to prepare compounds according to theinvention e.g. from starting materials disclosed in the patents referredto above.

[0052] For example, amide prodrugs of pregabalin may be prepared byreacting pregabalin with an acid chloride in an ether e.g.tetrahydrofuran at ambient temperatures. A carboxylic acid group of theresulting prodrug may be converted to an ester group by reaction with analcohol e.g. by reaction with benzyl alcohol in the presence of1,3-dicyclohexyldiimide (DCC) and 4-dimethylaminopyridine (DMAP) in ahalogenated hydrocarbon solvent e.g. dichloromethane (DCM) at ambienttemperatures. (Acyloxy)alkyl carbamate prodrugs of pregabalin may beprepared by reacting pregabalin with an acyloxyalkyl p-nitrophenylcarbonate in an ether e.g. tetrahydrofuran at ambient temperatures.

[0053] These reactions are illustrated in the following reaction schemeby reference to preferred reagents and preferred final products (4), (5)and (6), it being understood that a similar scheme applies mutatismutandis to the use of other acyl chlorides, acyloxymethylene carbonatesand optionally esterifying reagents, for the preparation of other finalproducts of formula (III) above.

[0054] The compounds of the invention are expected to be useful in thetreatment of epilepsy. They may also be used as mimetic agents forneurodegenerative disorders. Such neurodegenerative disorders are, forexample, Alzheimer's disease, Huntington's disease, Parkinson's disease,and Amyotrophic Lateral Sclerosis. The present invention also coverstreating acute brain injury. These include but are not limited to:stroke, head trauma, and asphyxia. Stroke refers to a cerebral vasculardisease and may also be referred to as a cerebral vascular incident(CVA) and includes acute thromboembolic stroke. Stroke includes bothfocal and global ischemia. Also, included are transient cerebralischemic attacks and other cerebral vascular problems accompanied bycerebral ischemia such as in a patient undergoing carotid endarterectomyspecifically or other cerebrovascular or vascular surgical procedures ingeneral, or diagnostic vascular procedures including cerebralangiography and the like. Other incidents are head trauma, spinal cordtrauma, or injury from general anoxia, hypoxia, hypoglycemia,hypotension as well as similar injuries seen during procedures fromembole, hyperfusion, and hypoxia. Treatment with the present compoundscould also be useful in a range of incidents, for example, duringcardiac bypass surgery, in incidents of intracranial hemorrhage, inperinatal asphyxia, in cardiac arrest, and status epilepticus. A skilledphysician will be able to determine the appropriate situation in whichsubjects are susceptible to or at risk of, for example, stroke as wellas suffering from stroke for administration by methods of the presentinvention.

[0055] The compounds of the invention are also expected to be useful inthe treatment of depression. Depression can be the result of organicdisease, secondary to stress associated with personal loss, oridiopathic in origin. There is a strong tendency for familial occurrenceof some forms of depression suggesting a mechanistic cause for at leastsome forms of depression. The diagnosis of depression is made primarilyby quantification of alterations in patients' mood. These evaluations ofmood are generally performed by a physician or quantified by aneuropsychologist using validated rating scales, such as the HamiltonDepression Rating Scale or the Brief Psychiatric Rating Scale. Numerousother scales have been developed to quantify and measure the degree ofmood alterations in patients with depression, such as insomnia,difficulty with concentration, lack of energy, feelings ofworthlessness, and guilt. The standards for diagnosis of depression aswell as all psychiatric diagnoses are collected in the Diagnostic andStatistical Manual of Mental Disorders (Fourth Edition) referred to asthe DSM-IV-R manual published by the American Psychiatric Association,1994.

[0056] The present compounds are also expected to be useful in thetreatment of anxiety and of panic as demonstrated by means of standardpharmacological procedures.

[0057] The compounds of the invention are also expected to be useful inthe treatment of pain. Pain refers to acute as well as chronic pain.Acute pain is usually short-lived and is associated with hyperactivityof the sympathetic nervous system. Examples are postoperative pain andallodynia. Chronic pain is usually defined as pain persisting from 3 to6 months and includes somatogenic pains and psychogenic pains. Otherpain is nociceptive. Still other pain is caused by injury orinflammation of peripheral sensory nerves. It includes, but is notlimited to pain from peripheral nerve trauma, herpes virus infection,diabetes mellitus, causalgia, plexus avulsion, neuroma, limb amputation,and vasculitis. Neuropathic pain is also caused by nerve damage fromchronic alcoholism, human immunodeficiency virus infection,hypothyroidism, uremia, or vitamin deficiencies. Neuropathic painincludes, but is not limited to pain caused by nerve injury such as, forexample, the pain diabetics suffer from. Psychogenic pain is that whichoccurs without an organic origin such as low back pain, atypical facialpain, and chronic headache. Other types of pain are: inflammatory pain,osteoarthritic pain, trigeminal neuralgia, cancer pain, diabeticneuropathy, restless leg syndrome, acute herpetic and postherpeticneuralgia, causalgia, brachial plexus avulsion, occipital neuralgia,gout, phantom limb, burn, and other forms of neuralgia, neuropathic andidiopathic pain syndrome.

[0058] The present compounds are also expected to be useful in thetreatment of digestive disorders such as visceral pain, pain associatedwith cancer, the irritable bowel syndrome, infection and inflammation.

[0059] The present compounds can be prepared and administered in a widevariety of oral and parenteral dosage forms. Thus, they can beadministered by injection, that is, intravenously, intramuscularly,intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.Also, they can be administered by inhalation, for example, intranasally.Additionally, the compounds of the present invention can be administeredtransdermally. It will be obvious to those skilled in the art that thefollowing dosage forms may comprise as the active component either acompound of the invention or a corresponding pharmaceutically acceptablesalt.

[0060] For preparing pharmaceutical compositions from the presentcompounds, pharmaceutically acceptable carriers can be either solid orliquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. A solidcarrier can be one or more substances which may also act as diluents,flavouring agents, binders, preservatives, tablet disintegrating agents,or an encapsulating material.

[0061] In powders, the carrier is a finely divided solid that is in amixture with the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from five or ten toabout seventy percent of the active compound. Suitable carriers aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

[0062] For preparing suppositories, a low melting wax, such as a mixtureof fatty acid glycerides or cocoa butter, is first melted, and theactive component is dispersed homogeneously therein, as by stirring. Themolten homogenous mixture is then poured into convenient sized molds,allowed to cool, and thereby to solidify.

[0063] Liquid form preparations include solutions, suspensions, andemulsions, for example, water or water propylene glycol solutions. Forparenteral injection liquid preparations can be formulated in solutionin aqueous polyethylene glycol.

[0064] Aqueous solutions suitable for oral use can be prepared bydissolving the active component in water and adding suitable colorants,flavours, stabilising and thickening agents as desired.

[0065] Aqueous suspensions suitable for oral use can be made bydispersing the finely divided active component in water with viscousmaterial, such as natural or synthetic gums, resins, methylcellulose,sodium carboxymethylcellulose, and other well-known suspending agents.

[0066] Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilisers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilising agents, andthe like.

[0067] The pharmaceutical preparation is preferably in unit dosage form.In such form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

[0068] The quantity of active component in a unit dose preparation maybe varied or adjusted from 0.1 mg to 1 g according to the particularapplication and the potency of the active component. In medical use thedrug may be administered three times daily as, for example, capsules of100 or 300 mg. The composition can, if desired, also contain othercompatible therapeutic agents.

[0069] In therapeutic use, the compounds utilised in the pharmaceuticalmethod of this invention are administered at the initial dosage of about0.01 mg to about 100 mg/kg daily. A daily dose range of about 0.01 mg toabout 100 mg/kg is preferred. The dosages, however, may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe art. Generally, treatment is initiated with smaller dosages that areless than the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

[0070] Preparation of Reagents

[0071] Acetoxymethyl p-nitrophenyl Carbonate (1)

[0072] Carbonate 1 was prepared as described in J.Med.Chem, 1988, 31,318-322 (5.29 g, 98%). Its characteristics were described in J.Org.Chem,1997, 62, 1356-1362.

[0073] ν_(max)(film)/cm⁻¹ 1776 (C═O), 1526 (C═C, Ar).

[0074] δ_(H)(400 MHz; CDCl₃) 2.19 (3H, s, CH₃), 5.88 (2H, s, OCH₂O),7.42 (2H, d, J 9.6, p-NO₂ArH), 8.30 (2H, d, J 9.2, p-NO₂ArH).

[0075] 2,2-dimethylpropionyloxymethyl p-nitrophenyl Carbonate (2)

[0076] Carbonate 2 was also prepared as described in the above paper(1.16 g, 60%).

[0077] ν_(max)(film)/cm⁻¹ 1779, 1759 (C═O), 1530 (C═C, Ar).

[0078] δ_(H)(400 MHz; CDCl₃) 1.26 (9H, s, ^(t)butyl), 5.89 (2H, s,OCH₂O), 7.41 (2H, d, J 9.4, p-NO₂ArH), 8.30 (2H, d, J 9.2, p-NO₂ArH).

[0079] Benzoyloxymethyl p-nitrophenyl Carbonate (3)

[0080] Carbonate 3 was also prepared as described in the above paper(1.76 g, 85%).

[0081] ν_(max)(film)/cm⁻¹ 1778, 1740 (C═O), 1525 (C═C Ar).

[0082] δ_(H)(400 MHz; CDCl₃) 6.14 (2H, s, OCH₂O), 7.42 (2H, d, J 9.2,p-NO₂ArH), 7.49 (2H, t, J 8.0, ArH), 7.64(1H, t, J 7.6, ArH), 8.12 (2H,d, J 7.2, ArH) 8.29 (2H, d, J 9.2, p-NO₂ArH).

[0083] The invention will now be further described with reference to thefollowing Examples.

EXAMPLE 1

[0084] (S)-3-(Benzoylaminomethyl)-5-methylhexanoic acid (4)

[0085] Benzoyl chloride (0.88 ml, 7.6 mmol) was added to a stirredsuspension of pregabalin (1.0 g, 6.3 mmol) in THF (80 ml) at roomtemperature under argon and the reaction mixture was stirred for 18hours. The reaction mixture was then filtered and concentrated in vacuo.The residue was chromatographed (SiO₂, heptane-ethyl acetate, 1:1 to3:7) to give 4 (0.78 g, 47%).

[0086] ν_(max)(film)/cm⁻¹ 1705, 1634 (C═O), 1547 (C═C, Ar).

[0087] δ_(H)(400 MHz; CDCl₃) 0.92 (3H, d, J 6.8, CH₃), 0.94 (3H, d, J7.6, CH₃), 1.20-1.30 (2H, m, CH₂CH(CH₃)₂), 1.69-1.79 (1H, m, CH(CH₃)₂),2.20-2.30 (1H, m, CHCH₂CH(CH₃)₂), 2.35 (1H, dd, J 8.1, 14.7,CH_(A)H_(B)COOH), 2.45 (1H, dd, J 14.7, 4.2, CH_(A)H_(B)COOH), 3.38-3.43(1H, m, CH_(A)H_(B)NH), 3.57-3.63 (1H, m, CH_(A)H_(B)NH), 6.63 (1H, bs,NH), 7.41-7.57 (3H, m, ArH), 7.78 (2H, d, J 7.6, ArH).

EXAMPLE 2

[0088] (S)-Benzyl 3-(benzoylaminomethyl)-5-methylhexanoate (5)

[0089] Benzyl alcohol (0.31 g, 3.0 mmol) was added to a stirred mixtureof (S)-3-(benzoylaminomethyl)-5-methylhexanoic acid 4 (0.78 g, 3.0mmol), 1,3-dicyclo-hexylcarbodiimide (0.61 g, 3.0 mmol), and4-dimethylaminopyridine (0.36 g, 3.0 mmol) in dichloromethane (40 ml)and the mixture was stirred for 18 hours. The reaction mixture was,filtered and concentrated in vacuo. The residue was chromatographed(SiO₂, heptane-ether, 1:0 to 75:25) to give 5 (0.83 g, 79%).

[0090] ν_(max)(film)/cm⁻¹ 1732, 1640 (C═O).

[0091] δ_(H)(400 MHz; CDCl₃) 0.89 (3H, d, J 7.2, CH₃), 0.91 (3H, d, J6.8, CH₃), 1.19-1.30 (2H, m, CH₂CH(CH₃)₂), 1.64-1.75 (1H, m, CH(CH₃)₂)2.23-2.35 (1H, m, CHCH₂CH(CH₃)₂), 2.39 (1H, dd, J 15.4, 7.3,CH_(A)H_(B)COOH), 2.47 (1H, dd, J 15.4, 4.9, CH_(A)H_(B)COOH), 3.34-3.39(1H, m, CH_(A)H_(B)NH), 3.52-3.58 (1H, m, CH_(A)H_(B)NH), 5.08 (2H, s,ArCH₂O), 6.64 (1H, bt, NH, 7.27-7.38 (5H, m, ArH, 7.39-7.50 (3H, m,ArH), 7.75 (2H, d, J 7.2, ArH).

EXAMPLE 3

[0092](S)-3-[N-(acetoxymethyleneoxycarbonyl)aminomethyl]-5-methylhexanoic Acid(6)

[0093] The carbonate 1 (1.0 g, 3.9 mmol) and pregabalin (0.62 g, 3.9mmol) were stirred in THF (60 ml) at room temperature for 48 hours. Thereaction mixture was taken up in ethyl acetate (250 ml) and washed withwater (200 ml), 1N HCl (200 ml), dried (MgSO₄) and concentrated invacuo. The residue was purified by column chromatography (SiO₂, heptane,then heptane-ethyl acetate, 1:1) to give (6) (0.18 g, 17%).

[0094] ν_(max)(film)/cm⁻¹ 1715 (C═O).

[0095] δ_(H)(400 MHz; CDCl₃) 0.91 (3H, d, J 6.8, CH₃), 0.91 (3H, d, J6.8, CH₃), 1.10-1.30 (2H, m, CH₂CH(CH₃)₂), 1.60-1.71 (1H, m, CH(CH₃)₂),2.12 (3H, s, COCH₃), 2.15-2.35 (1H, m, CHCH₂CH(CH₃)₂), 2.27 (1H, dd, J15.0, 8.0, CH_(A)H_(B)COOH), 2.37 (1H, dd, J 14.8, 4.4,CH_(A)H_(B)COOH), 3.10-3.17 (1H, m, CHHNH), 3.30-3.36 (1H, m, CHHNH),5.28 (1H, bs, NH), 5.71 & 5.75 (OCH₂O).

[0096] From reagents 2 and 3 there may correspondingly be prepared(S)-3-[N-((2,2-dimethylpropionyloxymethylenoxy)carbonyl)aminomethyl)-5-methyl-hexanoicacid and(S)-3-[N-(benzoyloxymethyleneoxycarbonyl)aminomethyl]-5-methylhexanoicacid.

1. A compound of the formula (III)

in which: P is hydrogen or methyl; Q is a labile amine- or amide-formingorganic group that becomes removed in the human or animal body; R¹ isstraight or branched C₂-C₆ alkyl, C₃-C₆ cycloalkyl or phenyl; R² ishydrogen or methyl; and R³ is hydrogen, methyl or carboxyl; and R⁴ ishydrogen or a labile ester-forming group selected from substituted andunsubstituted C₁-C₆ alkyl, benzyl and phenyl groups that become removedin the human or animal body, or a pharmaceutically acceptable salt ofany salt-forming compound within the above class, but excludingcompounds in which R₁ is phenyl and R², R³ and R⁴ are each hydrogen. 2.The compound of claim 1, in which R⁴ is hydrogen.
 3. The compound ofclaim 1, in which R⁴ is other than hydrogen and is more labile than Q.4. The compound of claim 3, in which R⁴ is methyl or t-butyl.
 5. Thecompound of claim 1, wherein Q can be removed hydrolytically underphysiological conditions.
 6. The compound of claim 1, wherein Q can beremoved enzymatically under physiological conditions.
 7. The compound ofclaim 1, wherein Q is

in which: R⁵ is hydrogen, straight or branched chain C₁-C₆ alkyl, phenylor benzyl in which the benzene ring may be substituted or unsubstituted;and Y is hydrogen, straight or branched chain C₁-C₆ alkyl, or —CH₂CO₂R⁶in which R⁶ represents straight or branched chain C₁-C₆ alkyl.
 8. Thecompound of claim 7, wherein R⁵ represents t-butyl, benzyl or phenyl. 9.The compound of claim 1, wherein Q is selected from

in which: R⁷ is hydrogen, straight or branched chain C₁-C₆ alkyl, phenylor benzyl in which either or each benzene ring may be substituted orunsubstituted; and X represents a phenyl group or any of the side chainsof the 20 naturally encoded α-amino acids.
 10. The compound of claim 1,wherein Q is

wherein R⁷ is methyl, t-butyl or phenyl.
 11. A compound of the formula(IV)

in which P, Q and R⁴ have the meanings given in claim 1, or apharmaceutically acceptable salt of any salt-forming compound within theabove class.
 12. The compound of claim 11, in which R⁴ is hydrogen. 13.The compound of claim 11, in which R⁴ is other than hydrogen and is morelabile than Q.
 14. The compound of claim 13, in which R⁴ is methyl ort-butyl.
 15. The compound of claim 11, wherein Q can be removedhydrolytically under physiological conditions.
 16. The compound of claim11, wherein Q can be removed enzymatically under physiologicalconditions.
 17. The compound of claim 11, wherein Q is

in which: R⁵ is hydrogen, straight or branched chain C₁-C₆ alkyl, phenylor benzyl in which the benzene ring may be substituted or unsubstituted;and Y is hydrogen, straight or branched chain C₁-C₆ alkyl, or —CH₂CO₂R⁶in which R⁶ represents straight or branched chain C₁-C₆ alkyl.
 18. Thecompound of claim 17, wherein R⁵ represents t-butyl, benzyl or phenyl.19. The compound of claim 11, wherein Q is selected from

in which: R⁷ is hydrogen, straight or branched chain C₁-C₆ alkyl, phenylor benzyl in which either or each benzene ring may be substituted orunsubstituted; and X represents a phenyl group or any of the side chainsof the 20 naturally encoded α-amino acids.
 20. The compound of claim 11,wherein Q is

wherein R⁷ is methyl, t-butyl or phenyl.
 21. A compound selected from(S)-3-(Benzoylaminomethyl)-5-methylhexanoic acid; (S)-Benzyl3-(acylaminomethyl)-5-methylhexanoate;(S)-3-[N-(acetoxymethyleneoxycarbonyl)aminomethyl]-5-methylhexanoicacid;(S)-3-[N-((2,2-dimethylpropionyloxy)methyleneoxycarbonyl)-amino-methyl]-5-methylhexanoicacid;(S)-3-[N-(benzoyloxymethyleneoxycarbonyl)aminomethyl]-5-methyl-hexanoicacid; and pharmaceutically acceptable salts of any of the above.
 22. Amethod for making a compound of the formula (III) or salt thereof, asdefined in claim 1, above, which comprises: coupling a compound of theformula:

in which P and R¹-R⁴ have the meanings given in claim 1 and in whichsaid compound is in the form of a free base or an ammonium salt with acompound of the formula

or QCl where Q has the meaning given in claim
 1. 23. The method of claim22, in which the compound (V) is a carboxylic acid and comprising thefurther step of esterifying the carboxyl group with a substituted orunsubstituted C₁-C₆ alkanol, benzyl alcohol or phenol.
 24. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of theformula (III)

in which: P is hydrogen or methyl; Q is a labile amine- or amide-formingorganic group that becomes removed in the human or animal body; R¹ isstraight or branched C₂-C₆ alkyl, C₃-C₆ cycloalkyl or phenyl; R² ishydrogen or methyl; and R³ is hydrogen, methyl or carboxyl; and R⁴ ishydrogen or a labile ester-forming group selected from substituted andunsubstituted C₁-C₆ alkyl, benzyl and phenyl groups that become removedin the human or animal body, or a pharmaceutically acceptable salt ofany salt-forming compound within the above class, but excludingcompounds in which R₁ is phenyl and R², R³ and R⁴ are each hydrogen. 25.A method for treating epilepsy comprising administering atherapeutically effective amount of a compound according to claim 1 to ahuman or animal in need of said treatment.
 26. A method for treatingfaintness attacks, hypokinesia and cranial disorders comprisingadministering a therapeutically effective amount of a compound accordingto claim 1 to a human or animal in need of said treatment.
 27. A methodfor treating a neurodegenerative disorder comprising administering atherapeutically effective amount of a compound according to claim 1 to ahuman or animal in need of said treatment.
 28. A method for treatingdepression comprising administering a therapeutically effective amountof a compound according to claim 1 to a human or animal in need of saidtreatment.
 29. A method for treating anxiety comprising administering atherapeutically effective amount of a compound according to claim 1 to ahuman or animal in need of said treatment.
 30. A method for treatingpanic comprising administering a therapeutically effective amount of acompound according to claim 1 to a human or animal in need of saidtreatment.
 31. A method for treating pain comprising administering atherapeutically effective amount of a compound according to claim 1 to ahuman or animal in need of said treatment.
 32. A method for treating aneuropathological disorder comprising administering a therapeuticallyeffective amount of a compound according to claim 1 to a human or animalin need of said treatment.
 33. A method for treating digestive disordercomprising administering a therapeutically effective amount of acompound according to claim 1 to a human or animal in need of saidtreatment.